Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-10-07
2003-03-18
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S213010, C514S217010, C514S217020, C540S523000, C540S593000, C540S594000, C540S595000
Reexamination Certificate
active
06534496
ABSTRACT:
This Application is National Stage of International Application Ser. No. PCT/JP98/01753, filed Apr. 16, 1998.
TECHNICAL FIELD
The present invention relates to a medicine and, more particularly, to a thermogenic agent (thermogenesis accelerator) for use as a prophylactic and/or treating drug for obesity and obesity-associated disease and its active compound, namely an aminoketone derivative or a salt thereof.
BACKGROUND ART
As treating drugs for obesity, centrally-acting anorexics such as mazindol have been used-clinically However, central anorexics have gastrointestinal side effects such as nausea and vomiting in addition to central side effects such as addiction and, therefore, are indicated only in limited cases, e.g. advanced obesity.
On the other hand, &bgr;3 adrenergic receptor agonists have been proposed as peripherally-acting antiobesity drugs [Nature, 309, 163-165, 1984; J. Med. Chem., 35, 3081-3084, 1992, etc.]. However, mutations of the &bgr;3 adrenergic receptor gene have been reported in a fairly large number of obese persons (New Engl. J. Med., 333, 343-347, 1995; Lancet, 346, 1433-1434, 1995; Biochem. Biophys. Res. Commun., 215, 555-560, 1995) and it is logical to assume that the antiobesity effect of any &bgr;3 adrenergic receptor agonist is self-limited.
As synthetic drugs, aminoketone derivatives having a variety of biological and pharmacological activities have been proposed (Japanese Patent Unexamined Publication No. 140149/1993, WO 9307140, EP 560235, EP 562832, Japanese Patent Unexamined Publication No. 169569/1990, U.S. Pat. No. 5,106,856, Japanese Patent Unexamined Publication No. 22333/1979, Japanese Patent Unexamined Publication No. 167546/1984, EP-A-0378207, Japanese Patent Unexamined Publication No. 206875/1994, Japanese Patent Unexamined Publication No. 206854/1995, Japanese Patent Unexamined Publication No. 309835/1995, WO 9103243, Khim.-Farm., Zh., 21, 569, (1987), Chem. Abstr., 89, 36594y (1978), Journal of the Pharmaceutical Society of Japan, 97, 540 (1977), EP 163537, Chem. Abstr., 91, 211631y (1979), Helvetica Chimica Acta, 51, 1616 (1968), Japanese Patent Unexamined Publication No. 97952/1977, Japanese Patent Unexamined Publication No. 7185/1984, FR-M3635, Chem. Abstr., 67, 54087k (1967), 68, 105121x (1968), 75, 88548s (1971), 76, 153682t (1972)). However, none of the literature discloses, or even suggests, that such derivatives ever have activity validating their use as prophylactic and/or treating drugs for obesity or obesity-associated disease, as lipolytic agents, or as thermogenic agents.
For example, Japanese Patent Unexamied Publication No. 140149/1993 describes a fused heterocyclic derivative of the following chemical formula or a salt thereof as a cholinesterase inhibitor:
wherein X represents R
1
—N< (R
1
represents hydrogen, a hydrocarbon group which may be substituted, or an acyl group which may be substituted), oxygen, or sulfur; R
2
reprehsents hydrogen or a hydrocarbon group which may be substituted; ring A represents a benzene ring which may be substituted; k represents an integer of 0-3; m represents an integer of 1-8; and n represents an integer of 1-6. Spedifically described is a compounds of the following formula:
WO 9307140 discloses a compound of the following formula as a cholinesterase inhibitor:
wherein ring A represents benzo, thieno, pyrido, pyrazino, pyrimido, furano, seleno, pyrrolo, thiazolo, or imidazolo; R
1
represents phenyl, phenyl(C
1-6
)alkyl, cinnamyl, or heteroarylmethyl (heteroaryl=imidazolo, thiazolo, thieno, pyrido, or isoxazolo); said phenyl and heteroaryl may each have 1 or2 substituent groups selected,from the class consisting of (C
1-6
)alkyl, (C
1-6
) alkoxy, and halogen; R
2
and R
3
independently represent hydrogen, (C
1-6
)alkoxy, or (C
1-6
)alkyl may have 1-3 substituent groups selected from fluorine, benzyloxy, hydroxy, phenyl, benzyl, halogen, nitro, cyano, CO
2
R
4
, CONHR
4
, NR
4
R
5
, NR
4
COR
5
, and SO
p
CH
2
Ph (where p represents 0, 1, or 2); or R
2
and R
3
may jointly and in combination with the adjacent carbon atom form a 5- or 6-membered ring (where the ring atoms are selected from the class consisting of carbon, nitrogen, and oxygen; e.g. methylenedioxy, ethylenedioxy, or a lactam, ring); R
4
and R
5
independently represent hydrogen or (C
1-6
)alkyl, or R
4
and R
5
of NR
4
R
5
may jointly and in, combination with the adjacent nitrogen form a 4- through 8-membered ring containing at least one nitrogen atom (the other ring atoms are carbon and oxygen and/or nitrogen); R
4
and R
5
of NR
4
COR
5
may jointly and in combination with the adjacent nitrogen and carbon atoms form a 4- through 8-membered lactam ring; X represents nitrogen or CH; Y represents oxygen, sulfur, or NR
6
; R
6
represents hydrogen, (C
1-6
)alkyl, CO(C
1-6
)alkyl, or SO
2
-phenyl (the phenyl may have 1 to 5 substituent groups independently selected from among (C
1-4
)alkyl species); n represents an integer of 1 through 4; q in n occurrences independently represents 1 or 2; z represents oxygen or sulfur. The following compound is typically disclosed as a cholinesterase inhibitor:
EP 560235 discloses a fused heterocyclic ketone derivative of the following formula or its salt as a cholinesterase inhibitor:
wherein R
1
represents hydrogen, a hydrocarbon group which may be substituted, or an acyl group which may be substituted; ring A represents a benzene ring which may be further substituted; n represents an integer of 1 through 10; R
2
, R
3
, and R
4
may be the same or different and each represents hydrogen or a hydrocarbon group which may be substituted; R
3
and R
4
may jointly and in combination with the adjacent nitrogen atom form a heterocyclic group which may be substituted; R
2
may not be the same in n occurrences; k represents an integer of 0 to 3; m represents an integer of 1 to 8; provided, however, that when k=0 and m=2, n>1. Specifically, the compound of the following formula is disclosed as a cholinesterase inhibitor:
EP 562832 discloses a compound of the formula:
wherein R
1
and R
2
independently represent hydrogen or an organic group; p represents 0, 1, 2, or 3; U represents —CO— or —CH(OR
3
)— (where R
3
represents hydrogen or a hydroxy-protecting group); V represents an aliphatic hydrocarbon group which may be unsaturated; W represents a nitrogen-containing group. Specifically, the compound of the following formula is mentioned as a cholinesterase inhibitor:
Japanese Patent Unexamined Publication No. 169569/1990 discloses acyclic amine derivative of the following formula or a pharmacologically acceptable salt thereof:
where J represents,
(a) (1) phenyl, (2) pyridyl, (3) pyrazyl, (4) quinolyl, (5) cyclohexyl, (6) quinoxalyl, or (7) furyl, each substituted or unsubstituted,
(b) a univalent or bivalent group, the phenyl moiety of which may be substituted, which is selected from the class consisting of (1) indanyl, (2) indanonyl, (3), indenyl, (4) indenonyl, (5) indandionyl, (6) tetralonyl, (7) benzosuberonyl, (8) indanolyl, (9) a group of the formula:
(c) a univalent group derived from a cyclic amide compound,
(d) a lower alkyl group, or
(e) a group of the formula R
1
—CH═CH— (where R
1
represents hydrogen or lower alkoxycarbonyl);
B represents a group of the formula —(C(R
2
)H)
n
—, a group of the formula —CO—(C(R
2
)H)
n
—, a group of the formula —NR
2
—(C(R
2
)H)
n
— (where R
2
represents hydrogen, lower alkyl, acyl, lower alkylsulfonyl, phenyl which may be substituted, or benzyl), a group of the formula —CO—NR
4
—(C(R
2
)H)
n
— (where R
4
represents hydrogen, lower alkyl, or phenyl), a group of the formula —CH═CH—(C(R
2
)H)
n
—, a group of the formula —O—COO—(C(R
2
)H)
n
—, a group of the formula —O—CO—NH—(C(R
2
)H)
n
—, a group of the formula —NH—CO—(C(R
2
)H)
n
—, a group of the formula —CH
2
—CO—NH—((R
2
)H)
n
—, a group of the formula —CO—NH—(C(R
2
)H)
n
—, a group of the formula —C(OH)H—(C(R
2
)H)
n
— (in each of the above formulas, n represents an integer of 0-10; R
2
represents hydrogen or methyl in the sense
Fujisawa Yukio
Furuyama Naoki
Ishihara Yuji
Chao Mark
Coleman Brenda
Ramesh Elaine M.
Takeda Chemical Industries, Inc.
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